title: PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum.
abstract: The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a critical virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here we show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an orthologue of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Human Parasite Molecular and Cell Biology, Institut Pasteur of Shanghai, Shanghai 200031, China. lbjiang@ips.ac.cn
authors.forename: Lubin
authors.initials: L
authors.lastname: Jiang
authors.forename: Jianbing
authors.initials: J
authors.lastname: Mu
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Ni
authors.forename: Prakash
authors.initials: P
authors.lastname: Srinivasan
authors.forename: Kempaiah
authors.initials: K
authors.lastname: Rayavara
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yang
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.forename: Guiying
authors.initials: G
authors.lastname: Wei
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Jing
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Wakabayashi
authors.forename: Abhisheka
authors.initials: A
authors.lastname: Bansal
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: José M C
authors.initials: JM
authors.lastname: Ribeiro
authors.forename: Artur
authors.initials: A
authors.lastname: Scherf
authors.forename: L
authors.initials: L
authors.lastname: Aravind
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.forename: Louis H
authors.initials: LH
authors.lastname: Miller
mesh_terms: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism / Q000469:parasitology; D020868:Gene Silencing; D017125:Genes, Protozoan / Q000235:genetics; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D007438:Introns / Q000235:genetics; D008239:Lysine / Q000378:metabolism; D017780:Malaria Vaccines / Q000235:genetics; D008745:Methylation; D010963:Plasmodium falciparum / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics; D014157:Transcription Factors; D024363:Transcription Initiation Site; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics*
chemical_list: C490910:ASH1 protein, Drosophila; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006657:Histones; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors; D037521:Virulence Factors; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D008239:Lysine